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Diffuse idiopathic skeletal hyperostosis: Clinical features and pathogenic

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Article  in  Nature Reviews Rheumatology · November 2013

DOI: 10.1038/nrrheum.2013.165 · Source: PubMed

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 REVIEWS
Diffuse idiopathic skeletal hyperostosis:
clinical features and pathogenic mechanisms
Reuven Mader, Jorrit-Jan Verlaan and Dan Buskila
Abstract | Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic condition characterized by the
ossification and calcification of ligaments and entheses. DISH is observed on all continents and in
all races, but most commonly in men over 50 years of age. Although DISH is asymptomatic in most
individuals, the condition is often an indicator of underlying metabolic disease, and the presence of spinal
or extraspinal ossifications can sometimes lead to symptoms including pain, stiffness, a reduced range of
articular motion, and dysphagia, as well as increasing the risk of unstable spinal fractures. The aetiology
of DISH is poorly understood, and the roles of the many factors that might be involved in the development
of excess bone are not well delineated. The study of pathophysiological aspects of DISH is made difficult
by the formal diagnosis requiring the presence of multiple contiguous fully formed bridging ossifications,
which probably represent advanced stages of DISH. In this Review, the reader is provided with an up-to-
date discussion of the epidemiological, aetiological and clinical aspects of DISH. Existing classification
criteria (which, in the absence of diagnostic criteria, are used to establish a diagnosis of DISH) are also
considered, together with the need for modified criteria that enable timely identification of early phases in
the development of DISH.
Mader, R. et al. Nat. Rev. Rheumatol. advance online publication 5 November 2013; doi:10.1038/nrrheum.2013.165

Introduction
Diffuse idiopathic skeletal hyperostosis (DISH) is a direct consequence of DISH, bone depositions may lead
poorly understood, systemic condition characterized by to biomechanical changes of the musculoskeletal system
progressive calcification and ossification of ligaments and/or the formation of obstructive cervical masses.6,7
and entheses. Although the first description of DISH (by In this Review, the current understanding of DISH is
Forestier and Rotes-Querol using the dated term ‘anky- discussed with a special focus on epidemiology, aeti-
losing hyperostosis’) dates back to 1950,1 a large body of ology, clinical manifestations and treatment options.
evidence shows DISH to be of more ancient origin.2 The Furthermore, the present criteria for the definition of
formal diagnosis of DISH is established when simple DISH are scrutinized, and suggestions for a new and
descriptive morphological abnormalities of the thoracic improved version proposed.
spine are observed radiologically (Figure 1). Several
names have been previously proposed for the collection Epidemiology
of these features, including senile vertebral ankylos- Historical notes
ing hyper­ostosis, spondylitis deformans, spondylosis Macroscopic examinations of skeletal remains from
hyperostotica and spondylitis ossificans ligamentosa.3 humans living in medieval and more ancient times
However, the generally accepted current name—diffuse show DISH to be particularly prevalent in individuals
idiopathic skeletal hy­p erostosis—better reflects the of high social status, even when taking into account
Rheumatic Diseases
systemic nature of the condition and the paucity of the lon­g evity of elite groups. 8,9 Features suggestive Unit, Ha’Emek Medical
kn­owledge regarding its aetiology. of DISH have also been found in the skeleton of the Centre, Afula 18101,
Israel (R. Mader).
Because DISH is a largely asymptomatic condition, Egyptian pharaoh Ramses II and in Neanderthals living University Medical
with most affected individuals not aware of its presence, 50,000 years ago.10,11 Factors suggested to have contrib- Centre Utrecht,
it has not received much attention from clinicians and uted to the development of DISH in privileged ancient 3584 CX Utrecht,
The Netherlands
re­searchers. In addition, some studies have suggested that indivi­duals include a ­protein-rich diet, sedentary work (J.‑J. Verlaan).
DISH is of little clinical relevance.4 Increasing evidence, and obesity.12 The marked prevalence of DISH in medi- Department of
Medicine, H. Soroka
however, shows DISH to be an indicator for a number eval clergymen prompted some authors to relate the Medical Centre, Ben
of pathological conditions. The presence of DISH may development of DISH to ‘a monastic way of life’ and Gurion University of the
indicate underlying metabolic derangement and is view it as an ‘occupa­tional disease’.13,14 However, as cri- Negev, Beer Sheva
84101, Israel
associ­ated with cardiovascular disease.5 Moreover, as a teria to establish the diagnosis of DISH have not always (D. Buskila).
been applied uniformly (currently the classification
Correspondence to:
Competing interests by Resnick et al.3 from 1976 is most commonly used R. Mader
The authors declare no competing interests. to define the disease), some caution is advised when [email protected]

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Key points than elsewhere, publications have confirmed its presence

across all continent­s (Antarctica excluded).7
■■ Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by entheseal
ossification and/or calcification involving mainly the thoracic spine
As the natural course of DISH is typically benign,
■■ Peripheral joints and adjacent entheses can also be involved most individuals affected do not seek medical help, and
■■ The pathogenesis of DISH is not clear, but several factors may promote the the diagnosis is often established during the work-up for
differentiation of mesenchymal cells into bone-forming cells other medical conditions.19 A reliable estimation of the
■■ DISH is often associated with a variety of metabolic derangements, which may prevalence of DISH for a general population is therefore
increase cardiovascular morbidity not possible. Despite this lack of definitive baseline data,
■■ Patients with DISH also have an increased risk of complicated spinal fractures, some researchers predict a steep increase in the preva­
with associated morbidities
lence of DISH in Western countries, owing to the wide­
spread presence of risk factors for its development,
notably obesity, diabetes mellitus, hypertension and
a b
increased life expectancy.20,21

Clinical manifestations
Spinal involvement
Radiological characteristics
DISH is a condition that mainly affects the elderly popu-
lation. DISH has some peculiarities that allow its charac­
terization as a distinct clinical entity and differentiate
it from spondylosis.22 First, unlike spondylosis, DISH
frequently (and to date by definition) involves the tho-
racic spine, which is not usually involved in spondylosis
until late stages. Second, the intervertebral disc height
is usually preserved in patients with DISH, whereas it is
reduced in individuals with spondylosis.3 These differ-
ences are probably a result of the different targets of the
pathological processes. Indeed, in spondylosis, the main
target is the cartilage of the intervertebral discs, whereas
in DISH the target is the enthesis (with sparing of the
Figure 1 | The characteristic radiological features of DISH. intervertebral discs).3,23 Third, the osteophytes in spon-
a | Right-sided flowing osteophytes connecting thoracic dylosis are usually transverse, whereas the osteophytes in
vertebrae. b | Ossification of the anterior longitudinal DISH are coarse, vertical and bridging. Last, involvement
ligament. Abbreviation: DISH, diffuse idiopathic of the mobile cervical and lumbar spine in spondylosis is
skeletal hyperostosis. usually limited to the lower portions of these segments,
whereas in DISH the involvement is more extensive
comparing the results from older studies. Some histori- and can be associated with various complications.24,25
cal studies tentatively link DISH to physical impairment, Intervertebral disc lesions are as frequent in patients with
although these reports must be regarded as of mainly DISH as in patients with other conditions; however, they
anecdotal value.9, 15 tend to occur at an earlier age in patients with DISH.26

Modern era Pain and impaired mobility

Epidemiological data published in the past three decades Whether the radiographic spinal features of DISH
show DISH to be most prevalent in developed coun- described above result in clinical symptoms remains a
tries,16 although this apparent predominance might be matter of controversy, to the extent that some clinicians
due to the more frequent use of advanced radiological have considered DISH to be a state and not a disease.27
examinations in these countries than in others. The DISH was reported to be associated with morning stiff-
condition is unequally distributed between males and ness and spinal pain in over two-thirds of 200 patients
females (in a ratio of ~2:1), and its prevalence rapidly with the condition. In addition, a reduced range of
increases with age.17 In an epidemiological outpatient motion was described in nearly half of 21 patients.28,29
study, Weinfeld and colleagues found the prevalence of Furthermore, a study that examined the clinical features
DISH in patients over 50 years of age to be 25% for males of DISH reported that the degree of pain and disability
and 15% for females.18 A study aiming to find the preva- in these patients was higher than in healthy indivi­duals,
lence of DISH in the Netherlands by screening 501 chest and was similar to that of patients with spondylitis.30 By
radiographs obtained for unrelated medical conditions contrast, another study reported that the radiological
corroborated these results (17% of the individuals over findings of DISH are not associated with an increased
the age of 50 years in this study had DISH) and demon­ frequency of pain and, in the absence of complications,
strated that male gender and advancing age increase the have no clinical relevance.31 In addition, a study of self-
probability of the development of DISH.17 Although reported back pain in individuals with and without
DISH is more frequently observed in Western societies DISH suggested that the frequency of pain was actually

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reduced in patients with DISH. 19 It was shown, how­

ever, that 87 patients with DISH had more soft tissue
tender­ness and a lower functional status than 65 control
patients without DISH.32
The abundance of new bone formation that occurs
in DISH might be responsible for stiffening of the spine
(and of peripheral joints; see below) to the extent that
patients with DISH can assume the stooped postural
abnormalities typically observed in ankylosing spondy-
litis (AS), which can lead to an erroneous diagnosis of AS
instead of DISH.33 Interestingly, both DISH and AS are
characterized by ossification of spinal entheses, and the
mean yearly rate of progression of new bone formation
in patients with DISH, in the cervical and lumbar spine,
is similar to that of patients with AS.34
Although the thoracic spine is characteristically
affected by DISH, the spinal involvement of the condi-
tion is not limited to this region. Indeed, large protrud-
ing cervical enthesophytes can develop in patients with
DISH, and can cause severe complications, such as dys-
phagia, myelo­pathy, aspiration pneumonia, oesophageal
obstruction, stridor, hoarseness and thoracic outlet syn-
drome.25 Such enthesophytes can also make endotracheal
and endoscopic procedures difficult.25 In the lumbar
spine, the large enthesophytes can be bilateral and,
together with the excessive bone formation, can result
in spinal stenosis.35,36 Spinal stenosis can manifest itself
as cervical myelopathy or lumbar radiculopathy, often
with radicular claudication. Figure 2 | A typical spinal fracture in a patient with DISH.
The sagittal computed tomography image of the thoracic
spine of a 68-year-old female victim of a traffic accident
Fracture risk shows ossification of the anterior longitudinal ligament and
The presence of deformable and articulating structures in a hyperextension-type fracture. Abbreviation: DISH, diffuse
spinal segments (that is, the intervertebral disc and facet idiopathic skeletal hyperostosis.
joints) enables the healthy spinal column to flex, extend
and rotate in reaction to muscle contractions and exter- screened for traumatic injuries of the spinal column,
nal force. The energy experienced during a traumatic however minor, the presence of spinal ankylosis on
impact is normally distributed over multiple mobile seg- radiographs (due to AS or DISH) should lead to a high
ments, and luxations (dislocations) of the spine are there- index of suspicion for unstable fractures, loss of function
fore rare occurrences.37 In the ankylosed spine, however, and an increased risk for unfavourable outcome.
energy cannot be distributed over multiple levels and, as
a consequence, the spinal column in patients with DISH Extraspinal involvement
may fracture in a pattern similar to that observed in a The manifestations of DISH are not limited to the spine,
long bone.38 The number of consecutively fused spinal and peripheral joints and entheses are often affected.4,42–45
levels determines the length of the ‘lever arm’ on which Indeed, entheseal ossification and/or calcification in the
traumatic forces can act. Long lever arms can lead to proximity of peripheral joints, for example in tendons,
grossly displaced spinal fractures after a relatively minor ligaments and the joint capsule, can be observed in
trauma, such as a fall from a standing or sitting position patients with DISH. Owing to the age of the affected
or a low-speed motor vehicle collision (Figure 2).39 popu­l ations, DISH commonly coexists with osteo­
Besides displacement of spinal fractures, several arthritis (OA), which is characterized by joint-space nar-
studies have demonstrated that patients with fractures of rowing, subchondral sclerosis and osteophyte formation.
the ankylosed spine (due to DISH or AS) have a twofold However, it has been suggested that the involvement of
to fivefold higher risk of neurological deficits on hospital peripheral joints that are commonly affected by OA is
admission than patients with non-ankylosed spine frac- characterized in DISH by more prominent hyper­trophic
tures.37–40 Furthermore, patients admitted with fractures changes than those observed in OA, which leads to a
of the ankylosed spine were shown to have two times reduced range of motion in these joints. Furthermore,
as many secondary neurological deficits (often due to a OA‑like changes associated with DISH can involve
failure to recognize the presence of a fracture or a failure joints not usually affected by OA, such as the meta­
to properly immobilize the fractured spine), almost two carpophalangeal joints, elbow, shoulder and ankle.4,42–45
times as many complications, and a threefold to five- These features probably result from the ossification and
fold increase in mortality rate.39,41 Therefore, in patients calcification of entheses adjacent to joints.

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One unanswered question is what effect these changes pathogenesis. Moreover, familial clustering of the condi-
have on the clinical presentation of DISH. It could be tion and early onset (in the third decade of life) in some
assumed that damaged joints with OA‑like lesions will affected families have been observed, which are also
be pain­ful. However, few controlled studies have been suggestive of a genetic contribution to the disease.50,51
conducted to assess pain in hyperostotic peripheral joints, Studies in dogs have revealed the overall prevalence of
and they have yielded conflicting results. For example, canine DISH to be 3.8%, whereas in the Boxer breed it is
elbow pain was only slightly more prevalent in patients >40%, which further supports the existence of a genetic
with hyperostosis of the elbow (n = 48) than in controls component in the risk of developing DISH. 52 So far,
without elbow hyperostosis (n = 24); thus, this radiologi- however, only one potential susceptibility gene (namely
cal finding was considered to be of questionable clinical COL6A1, which encodes type VI collagen α chain) has
relevance.4 By contrast, the same group of investigators been identified.
concluded that shoulder hyperostosis in patients with Single nucleotide polymorphisms in COL6A1 have
DISH is a potential cause of pain.43 Thus, although the been reported in Japanese but not Czech patients with
clinical impact of hyperostosis in peripheral joints is not DISH.53,54 COL6A1 is also a known susceptibility gene
yet clear, limited range of motion and pain in OA‑atypical for ossification of the posterior longitudinal ligament
sites may draw attention to the possibility of DISH. (OPLL), a disorder that is closely associated with and
As mentioned above, calcification and ossification of can coexist with DISH. OPLL usually involves the cervi-
peripheral entheses, such as those in the heel, ribs and cal spine and, similarly to DISH, it affects the elderly,
pelvis, have been frequently observed in patients with more often males, and has been reported to be associated
DISH.46,47 Although some physicians have suggested the with low glucose tolerance and obesity.55 Nonetheless,
inclusion of symmetrical large enthesophytes in the clas- the association between COL6A1 variants and DISH was
sification of DISH, no studies have validated this pro- stronger among patients with DISH without OPLL than
posal.12,28 The clinical significance of these entheso­pathies in patients with concomitant DISH and OPLL, suggest-
is not clear, although in our experience the entheses can ing that OPLL associated with DISH might differ from
become tender and swollen. In a comparison of abnor- the common form of isolated OPLL.
malities at 14 pelvic sites in patients with DISH (n = 93) The protein encoded by COL6A1, type VI collagen α
versus patients with moderate to severe spondylosis, ossi- chain, is an extracellular matrix protein that might serve
fication of the iliolumbar, sacro­tuberous, and sacroiliac as a scaffold for osteoblastic or pre-osteoblastic cells or
ligaments, with enthesophytic overgrowth at the lesser chondrocytes that subsequently proceed to membra-
trochanter, proved to be significant in distinguishing nous or endochondral ossification.54 Thus, although the
between these entities.48 effects of COL6A1 variants on bone metabolism have not
been elucidated, it has been suggested that this protein
Heterotopic ossification might be involved in ectopic bone formation in DISH
Reflecting the systemic bone-forming nature of the and OPLL.
disease, patients with DISH have a greater propensity
than control individuals to develop heterotopic ossi- Metabolic factors
fications in response to local events, including joint Although DISH is a musculoskeletal condition, it has
replacement surgery.24 In some cases, these ossifications to be viewed as a systemic disease and has often been
can impair the proper functioning of the affected joint, linked to metabolic and constitutional factors, many of
and prophylactic treatment with irradiation or NSAIDs which form part of the metabolic syndrome.5 Indeed,
is indicated in these patients. It is currently not known DISH has been reported to be associated with obesity,
what causes the formation of heterotopic ossifications, high waist-to-hip circumference ratio, dyslipidemia,
although some physicians have speculated, having hypertension, glucose intolerance, type 2 diabetes,
observed the reoccurrence of these ossifications after hyper­uricaemia, hyperinsulinaemia and possibly ele-
surgical resection, that the surgical trauma itself induces vated growth hormone and insulin-like growth factor 1
ossification through as yet unknown pathways.49 (IGF‑1) levels.56–61 Owing to these metabolic derange-
ments, patients with DISH have an increased likeli-
Aetiology and pathogenesis hood of being affected by metabolic syndrome and an
The aetiology and pathogenesis of DISH are far from increased risk for the development of coronary artery
clear. However, DISH has to be considered a bone-­ disease and stroke.5,62
forming disease. Indeed, the hallmark of the condition is Excess body weight has been reported in patients with
new bone formation, in bones and especially in entheses. DISH since the early description by Forestier,1 and this
The enthesis is composed of fibroblasts, chondrocytes, finding has been reiterated in other studies.30,63 Moreover,
collagen fibres and calcified matrix; these components DISH has been associated with type  2 dia­b etes, 60
might be influenced by various mediators that can although other investigators have questioned the asso-
promote new bone formation in these sites. ciation.64 Both excess body weight and type 2 dia­betes
are often accompanied by hyperinsulinaemia, which has
Genetic factors also been reported in patients with DISH.56–58,65–67 Insulin
The variation in the prevalence of DISH throughout the has been shown to promote the differentiation of mesen-
world suggests that genetic factors might play a part in its chymal cells into chondrocytes in vitro,68 suggesting that

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hyperinsulinaemia might induce chondrogenesis and TGF-β1 PDGF-BB PGI2 ET-1

possibly subsequent ossification in ligaments (Figure 3).59

NFκB Low DKK-1

Growth hormone and IGF‑1
IGF-1
Growth hormone has the ability to promote bone
formation, either directly by stimulating osteoblast Osteoblastic differentiation Wnt–β catenin
and/or proliferation
proliferation or indirectly by promoting local IGF‑1 GH
production.61,69 IGF‑1 mediates the actions of growth
hormone on bone by stimulating the proliferation of
fibroblasts and chondrocytes.70 A study of 55 patients Vitamin D
Chondrogenesis New bone formation
with DISH, who were matched for age, sex, race, height and ossification
and weight to 54 control individuals and 63 patients
with OA, suggested that patients with DISH have a sta-
tistically significant increase in serum levels of growth Insulin Genetic factors
Entheseal calcification (COL6A1?)
hormone compared with controls, but similar levels to and ossification
patients with OA.57 Patients with DISH also have higher
growth hormone levels in their synovial fluid than in
Mesenchymal cell differentiation
their serum.71 Intra-erythrocyte growth hormone levels into fibroblasts and chondrocytes
might also be higher than serum levels, although it is MGP BMP2
not clear whether the transport and release of growth deficiency
hormone by erythrocytes affects bone physiology.72,73
Nonetheless, the anterior longitudinal ligament and Figure 3 | Suggested factors that promote entheseal calcification and ossification
the vertebral bodies in DISH have been shown to have in DISH. GH promotes osteoblastic differentiation and/or proliferation either
increased markers of vascular supply (increased numbers directly, or indirectly by promoting IGF‑1 production. NFκB activity is stimulated
of nutrient foramina), and thus it has been suggested by PDGF-BB and TGF‑β1 and promotes soft tissue ossification. ET‑1 and PGI2
that increased amounts of various growth factors, such may promote osteoblastic differentiation. Low DKK‑1 levels enhance the
as growth hormone, might be transported to these sites. activity of the Wnt–β-catenin pathway, which induces osteoblastic differentiation
and/or proliferation. MGP deficiency increases BMP2 activity, leading to the
differentiation of mesenchymal cells into chondrocytes and fibroblasts, which may
Vitamin A calcify. Insulin induces chondrogenesis and ossification. Abbreviations: BMP 2,
Similarly to growth hormone, vitamin A and its deriva- bone morphogenic protein 2; DISH, diffuse idiopathic skeletal hyperostosis;
tives have the ability to promote new bone forma- DKK‑1, Dickkopf‑related protein 1; ET‑1, endothelin 1; GH, growth hormone;
tion. However, whether vitamin A has a role in the IGF-1, insulin-like growth factor 1; MGP, matrix Gla protein; NFκB, nuclear factor
pathogenesis of DISH is controversial. Nonetheless, κB; PDGF-BB, platelet-derived growth factor BB; PGI2, prostaglandin I2; TGF‑β1,
several studies have reported higher vitamin A levels in transforming growth factor β1.
patients with DISH or have observed DISH-like mani-
festations in young patients treated with vitamin A or cells. In ligament mesenchymal cells, activation of NFκB
its derivatives.74–76 is associated with osteoblastic differentiation. 81 The
activity of NFκB can be stimulated by growth factors
Signalling pathways such as platelet-derived growth factor BB (PDGF-BB)
Wnt signalling and transforming growth factor β1 (TGF‑β1); higher
In recent years, the Wnt–β-catenin pathway has emerged levels of these factors were observed in non-ossified liga-
as an important regulator of many aspects of bone and ment tissue from patients with DISH and/or ossification
joint physiology. In particular, this pathway induces bone of the spinal ligaments than in tissue from patients with
formation, both by diverting the differentiation of mes- other spinal conditions.81 This study also found increased
enchymal cells away from chondrocytes and adipocytes alkaline phosphatase (ALP) activity in the ligament cells
towards osteoblasts and by inhibiting osteoblast apopto- from patients with DISH and/or ossification of the spinal
sis and osteoclastogenesis. Wnt signalling can be inhib- ligaments following in vitro culture, reflecting the matu-
ited by the endogenous secreted protein Dickkopf-related ration of these cells into osteoblasts.81 These findings hint
protein 1 (DKK-1; also known as Dickkopf‑1), the levels at a possible role for growth factor-induced NFκB signal-
of which have been investigated in patients with DISH. ling in the promotion of soft tissue ossification, although
A small cross-sectional study failed to show dif­ferences further studies are needed to confirm the relevance of the
in DKK-1 levels between people with DISH and healthy observed associations. Interestingly, both TGF‑β1 levels
individuals.77 However, low DKK-1 levels might have a and PDGF-BB signalling might be increased in type 2
role in the development of extensive bony spinal bridges diabetes,82,83 which might in part explain the association
in a subset of patients with DISH (Figure 3).78–80 between type 2 diabetes and DISH.

NFκB signalling BMP2 signalling

Nuclear factor κB (NFκB) regulates the expression of Bone morphogenic protein 2 (BMP2) and its receptors
several genes that are involved in the growth and division participate in the ligamentous ossification process by
of cells, and regulates the differentiation of multipotent inducing the differentiation of mesenchymal cells into

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Table 1 | Suggested main diagnostic features of DISH

Definition Number of vertebrae Peripheral enthesopathies SIJ involvement
connected by bony bridges
Resnick and Niwayama3 4 in the thoracic spine Not required Not involved
Arlet and Mazieres93 3 in the lower thoracic spine Not required Ossification in the vicinity
of the SIJ allowed
Utsinger28 Involvement of the SIJ is
Definite DISH 4 in the thoracolumbar spine Not required not an exclusion criterion
Probable DISH 2 in the thoracolumbar spine Bilateral enthesopathies
Possible DISH 2 in the thoracolumbar spine Not required
None Symmetrical enthesopathies preferably
in >2 anatomical sites
Rogers and Waldron14 3 in the thoracic spine Peripheral calcification or ossification No reference
of ligaments and/or entheses
Abbreviations: DISH, diffuse idiopathic skeletal hyperostosis; SIJ, sacroiliac joint.

fibroblasts and chondrocytes and by increasing ALP this segment of the spine. However, a lack of mobility
activity (Figure 3).84,85 The activity of BMP2 is inhibited cannot explain the involvement of more mobile seg-
by matrix Gla protein (MGP), and therefore deficiency ments, such as the cervical or lumbar spine, and further
of MGP or its defective carboxylation increases levels of studies are needed to solve this discrepancy.
active BMP2, with resultant excess new bone forma-
tion.61,86 Upregulation of the expression of BMP2 and Peripheral mechanisms
BMP4 mRNA has been observed following mechanical Mechanisms that underlie the pathogenesis of hyper-
stress in spinal ligament cells from patients with OPLL,87 trophic OA‑like changes in peripheral joints and the
and thus it is possible that this pathway might also be involvement in DISH of peripheral joints not typi-
involved in the ossification process in DISH. cally affected in primary OA have not been elucidated.
Beyond the hyperostotic processes described above, it
PGI2 and endothelin 1 has been suggested that these manifestations of DISH
Prostaglandin I2 (PGI2) is a potent inhibitor of bone might result from stiffening of capsules and ligaments
resorption, and endothelin 1 is a potent vasoactive around the joints and, as a result, increased intra-
peptide that might regulate ectopic calcification of the articular pressure.92 Further research will be needed to
vasculature. Besides its endothelial expression, endothe- confirm this hypothesis, as well as to elucidate the spinal
lin 1 is reportedly expressed in osteocytes, osteoblasts mechanisms of ossification, if we are to fully understand
and osteoclasts, and it may regulate the proliferation of the pathogenesis of DISH.
these cells.89,90 In vitro studies of cells harvested during
surgery from patients with OPLL and from control Diagnosis
indivi­duals showed that mechanical stress on OPLL Classification criteria
cells can enhance the production of PGI2 and endo­ Several sets of classification criteria have been proposed
thelin 1.88,89 Both of these molecules can induce, through for DISH (Table 1). The 1976 Resnick and Niwayama
various mechanisms, ALP activity and osteogenic criteria 3 require either ‘flowing’ coarse osteophytes
differen­tiation in spinal ligament cells. Endothelin 1 can connecting at least four contiguous vertebrae or ossi-
exert its activity directly by increasing the expression of fication of the anterior longitudinal ligament, together
osteogenic marker genes, such as those encoding ALP, with preserved intervertebral height and an absence of
type I collagen and osteocalcin. Furthermore, it can act apophyseal joint or sacroiliac joint (SIJ) involvement.3
indirectly by upregulating PGI2 expression (Figure 3).88,89 In 1985, Arlet and Mazieres93 lowered the threshold
It has been speculated that endothelin 1 and PGI2 might for the number of vertebrae bridged by flowing osteo-
have roles in the pathogenesis of DISH, although this phytes to three vertebrae in the lower thoracic spine. In
hypothesis awaits confirmation. their criteria, ossifications in the vicinity of the SIJ or
ilio­lumbar ligament are allowed, as long as the SIJ
Vascular and mechanical factors surface is not involved.93 Also in 1985, Utsinger further
One of the intriguing questions about DISH is the predi- extended the classification criteria to include peripheral
lection for ossification of the anterolateral aspect of the entheso­pathies.28 Using these criteria, a definite DISH
thoracic spine. Interestingly, involvement of the left side diagnosis can be established when thoracolumbar ossi-
of the thoracic spine has been described in a few case fication of at least four contiguous vertebrae is present;
reports of patients with a right-sided aorta, suggesting a probable diagnosis can be considered when two con-
that aortic pulsations prevent the characteristic enthe- tiguous vertebrae are involved and bilateral peripheral
seal calcification and ossification observed in DISH.91 In enthesopathies are also observed; and a possible diagno-
addition, the limited mobility of the thoracic spine has sis can be con­sidered either when two contiguous verte-
been suggested to be responsible for the predilection to brae are involved or when symmetrical enthesopathies

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are observed in the absence of spinal involvement (in Box 1 | Suggested therapeutic interventions in DISH
particular when they affect more than one anatomical
■■ Weight reduction and physical activity
site). The probable and possible categories may iden-
■■ Physical therapy
tify sets of patients who are more likely to have DISH ■■ Diet low in saturated fat and carbohydrate
or develop DISH later on in life, although currently ■■ Instruction in joint-protection techniques
there is no known established practical approach to ■■ Entheseal protection and local corticosteroid infiltration
the manage­ment of these patients. The exclusion cri- ■■ Local application of NSAIDs or capsaicin
teria proposed by Utsinger were abnormal disc space ■■ Analgesics
height and apophy­s eal joint ankylosis. 28 Another set ■■ Systemic NSAIDs
■■ Avoidance of thiazide diuretics and β‑adrenergic
of classification criteria was suggested by Rogers and
antagonists
Waldron.14 Again, the mandatory criteria for the diagno- ■■ Prevention of accidental falls and aspiration pneumonia
sis of DISH were right-sided hyperostosis of the thoracic ■■ Prevention of post-surgical heterotopic ossification
vertebrae associated with extraspinal and/or entheseal ■■ Surgical resection of cervical osteophytes (in extreme
calcification and ossification (Table 1).14 A study of the cases)
human skeletal remains of 253 individuals found dif- Abbreviation: DISH, diffuse idiopathic skeletal hyperostosis.
ferences in the preva­lence of definite DISH depending
on the criteria used. The prevalence ranged from 5.5%
by the Resnick criteria to 17% by the Rogers criteria. rate of new bone formation is similar to that observed
The extraspinal enthesophytes were found to be unreli­ in AS.34 Therefore, given the lack of disease-modifying
able in predicting DISH.2 None of the criteria sets used therapeutics, the treatment of DISH should be directed
so far attempted to incorporate the constitutional and towards the musculoskeletal manifestations, the associ-
metabol­ic de­rangements reported in DISH. ated metabolic and constitutional co-morbidities, and
the complications of the condition (Box 1).
Differential diagnosis
Owing to inconsistencies in the literature and a paucity Treatment of pain
of well-designed studies, no agreement has been Physical therapy to preserve mobility and alleviate pain
reached regarding the incorporation of clinical symp- is thought to be a reasonable approach. However, a
toms, extraspinal manifestations or associated con- small study on the effect of exercise therapy in patients
stitutional and metabolic conditions in the diagnosis with DISH did not show a significant improvement
of DISH.94 Other diseases that exhibit excessive bone in the range of spinal motion, except for lumbosacral
formation and entheseal involvement should be consid- flexion.97 A beneficial effect of chiropractic management
ered before a diagnosis of DISH is established. Being a was reported only in two case reports.98,99 By contrast,
disease most commonly observed in elderly individuals, a small uncontrolled study reported that patients with
DISH may frequently coexist with spondylosis and OA. DISH who have musculoskeletal pain could benefit from
Distinguishing between these entities is not always easy treatment with NSAIDs or heat therapy.100
but can be achieved by considering the different spinal The peripheral joints in patients with DISH are
and extraspinal manifestations (see above). DISH also affected in a similar manner to those in patients with OA
shares features with AS, including a tendency for ossi- (although with hypertrophic changes or the involvement
fication of ligaments and entheses, although in AS this of atypical sites). Therefore, given the lack of studies on
process is thought to occur through different, inflam- the medical treatment of DISH, suggested treatments for
matory mechanisms. DISH can be distinguished from OA can be cautiously adopted. Such approaches include
AS by the absence of SIJ involvement, the appearance evaluation of activities of daily living; instruction in joint
and angle of projection from the vertebrae of the osteo- protection techniques and use of physiotherapy; use of
phytes or syndesmophytes, the older age at presentation, oral NSAIDs, analgesics, tramadol and, when there is
the absence of apophyseal joint obliteration, the lack of evidence of OA lesions, chondroitin and glucosamine;
association with HLA‑B27 and the lower degree of pain and intra-articular corticosteroid injections. In patients
and discomfort.6,95 with OA, for some joints, topical application of capsaicin
and NSAIDs might be preferred over oral NSAIDs.101 In
Treatment fact, the use of locally acting NSAIDs could be as effec-
Approach to management tive as systemic therapy, at least in patients with knee
Data regarding therapeutic interventions in DISH are OA, and thus might be useful for the relief of pain in
very limited. Although patients with DISH are presum- the peripheral joints and the entheses in patients with
ably included in OA therapeutic trials, no reported thera- DISH.102 Painful entheses might also benefit from soft
peutic studies have specifically focused on this group of protections or local corticosteroid injections, although
patients. Interventions aimed at preventing the condi- no studies have yet investigated such approaches in
tion or arresting its progression are hampered by the long patients with DISH.
time period required for the development of the ver-
tebral bony bridges. It has been suggested that it takes Prevention and management of comorbidities
approximately 10 years from the start of the ossification The metabolic and constitutional abnormalities fre-
to its full radiological expression.96 In this regard, the quently observed in patients with DISH deserve attention

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© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS

for their effect on the risk of cardiovascular disease. symmetrical peripheral enthesopathies (in the absence of
Thus, physical activity, low intake of saturated fat and of spinal involvement) can be the only manifestation of the
carbo­hydrates, and weight reduction should be encour- condition. Furthermore, very little is known about
aged. Moreover, such strategies should help to reduce the aetiology, pathogenesis and associated conditions
hyperinsulinaemia, which is thought to have a role in the that, in our opinion, should be incorporated in future
pathogenesis of DISH. In addition, hypertensive patients definitions of the disease. Thus, we think that new diag-
with DISH should try to avoid medications that might nostic cri­teria should be established and validated, with
increase insulin resistance, such as thiazide diuretics and particular emphasis on early manifestation.
β‑adrenergic antagonists (β-blockers), and preferentially It is unlikely that the excessive bone formation can be
select medications that improve insulin resistance, such reversed, but with more knowledge it might be prevented.
as angiotensin-converting enzyme (ACE) inhibitors, To this end, large-scale epidemiological studies address-
calcium channel blockers and α‑adrenergic antagonists.103 ing the full clinical spectrum of DISH and its preva­
lence, natural course and outcome are needed. Moreover,
Surgery and complications explora­tion of the factors responsible for bone formation,
In the absence of traumatic fractures, surgical spinal inter- together with familial aggregation studies and the identi-
ventions are rarely needed in patients with DISH, except fication of genetic markers (haplotypes) associated with
in cases with severe spinal stenosis or large cervical osteo- DISH, might help to uncover the molecular basis of the
phytes. Two small case series have reported that patients ligamentous and entheseal ossification that characterizes
with large anterior cervical osteophytes causing dysphagia the condition. Such understanding might pave the way
or airway obstruction, who failed medical therapy, might to more targeted and effective therapies in the future.
benefit from surgical resection of the osteophytes.104,105 So, instead of merely symptomatic relief, future research
Finally, patients and physicians should be aware of, may offer a disease-modifying therapeutic approach to
and try to prevent, complications such as aspiration patients with DISH.
pneumonia, difficulties in endotracheal intubation or
upper gastro­intestinal endoscopy, and accidental falls. Conclusions
Prevention of heterotropic ossification using NSAIDs, DISH is a condition characterized by new bone forma-
vitamin K antagonists or irradiation should be considered tion, and constitutional and metabolic abnormalities.
in patients undergoing orthopaedic surgery (Box 1).106,107 Little is known about its pathogenesis, and suitable thera­
peutic approaches are unclear. A more comprehensive
Suggestions for future research definition of DISH, that preferably includes patients with
DISH is a clinical and radiological entity usually diag- early phase disease, and prospective studies in patients
nosed on radiographic grounds only. Nonetheless, DISH prone to develop the condition are needed to advance
should be considered an extensive proliferative musculo­ our understanding of this condition.
skeletal disease associated with clinical and metabolic
derangements. Owing to the limitations of the current Review criteria
definitions and classification criteria, the condition The articles cited in this Review were selected from the
cannot be diagnosed in its early stages. As a result, effec- authors’ personal library of articles on DISH. Selections
tive treatment to arrest or slow the progression of the were made on the basis of the expert opinions of
disease has never been investigated. We believe that large the authors.

1. Forestier, J. & Rotes-Querol, J. Senile ankylosing skeletal hyperostosis of the cervical spine: an 14. Rogers, J. & Waldron, T. DISH and the monastic
hyperostosis of the spine. Ann. Rheum. Dis. 9, underestimated cause of dysphagia and airway way of life. Int. J. Osteoarchaeol. 11, 357–365
321–330 (1950). obstraction. Spine J. 11, 1058–1067 (2011). (2001).
2. Van der Merwe, A. E., Maat, G. J. & Watt, I. 8. Weisz, G. M., Matucci-Cerinic, M., Lippi, D. & 15. Ullrich, H. [Goethe’s skull and skeleton] 60,
Diffuse idiopathic skeletal hyperostosis: Albury, W. R. The ossification diathesis in the 341–368 (2002).
Diagnosis in a palaeopathological context. medici family: DISH and other features. 16. Kiss, C. et al. Prevalence of diffuse idiopathic
Homo 63, 202–215 (2012). Rheumatol. Int. 31, 1649–1652 (2011). skeletal hyperostosis in Budapest, Hungary.
3. Resnick, D. & Niwayama, G. Radiographic and 9. Verlaan, J. J., Oner, F. C. & Maat, G. J. Diffuse Rheumatology (Oxford) 41, 1335–1336 (2002).
pathologic features of spinal involvement in idiopathic skeletal hyperostosis in ancient 17. Westerveld, L. A., van Ufford, H. M.,
diffuse idiopathic skeletal hyperostosis (DISH). clergymen. Eur. Spine J. 16, 1129–1135 (2007). Verlaan, J. J. & Oner, F. C. The prevalence of
Radiology 119, 559–568 (1976). 10. Chhem, R. K., Schmit, P. & Fauré, C. Did diffuse idiopathic skeletal hyperostosis in an
4. Beyeler, C. et al. Diffuse idiopathic skeletal Ramesses II really have ankylosing spondylitis? outpatient population in the Netherlands.
hyperostosis (DISH) of the elbow: A cause of A reappraisal. Can. Assoc. Radiol. J.  55, J. Rheumatol. 35, 1635–1638 (2008).
elbow pain? A controlled study. Br. J. Rheumatol. 211–217 (2004). 18. Weinfeld, R. M., Olson, P. N., Maki, D. D. &
31, 319–323 (1992). 11. Crubézy, E. & Trinkaus, E. Shanidar 1: a case of Griffiths, H. J. The prevalence of diffuse
5. Mader, R., Novofestovski, I., Adawi, M. & Lavi, I. hyperostotic disease (DISH) in the middle idiopathic skeletal hyperostosis (DISH) in two
Metabolic syndrome and cardiovascular risk in Paleolithic. Am. J. Phys. Anthropol. 89, 411–420 large american midwest metropolitan hospital
patients with diffuse idiopathic skeletal (1992). populations. Skeletal Radiol. 26, 222–225
hyperostosis. Semin. Arthritis Rheum. 38, 12. Giuffra, V. et al. Diffuse idiopathic skeletal (1997).
361–365 (2009). hyperostosis in the Medici, Grand Dukes of 19. Holton, K. F. et al. Diffuse idiopathic skeletal
6. Mader, R. et al. Extraspinal manifestations of Florence (XVI century). Eur. Spine J. hyperostosis and its relation to back pain among
diffuse idiopathic skeletal hyperostosis. 19 (Suppl. 2), S103–S107 (2010). older men: The MrOS study. Semin. Arthritis
Rheumatology 48, 1478–1481 (2009). 13. Waldron, T. DISH at merton priory: evidence for Rheum. 41, 131–138 (2011).
7. Verlaan, J. J., Boswijk, F. L., de Ru, J. A., a “new” occupational disease? BMJ 291, 20. Bray, G. A. & Bellanger, T. Epidemiology, trends,
Dhert, W. J. & Oner, F. C. Diffuse idiopathic 1762–1763 (1985). and morbidities of obesity and the metabolic

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© 2013 Macmillan Publishers Limited. All rights reserved
 REVIEWS

syndrome. Endocrine 29, 109–117 (2006). 40. Whang, P. G. et al. The management of spinal idiopathic skeletal hyperostos: A controlled
21. Mader, R. & Lavi, I. Diabetes mellitus and injuries in patients with ankylosing spondylitis or study. J. Rheumatol. 23, 672–676 (1996).
hypertension as risk factors for early diffuse diffuse idiopathic skeletal hyperostosis: A 59. Akune, T. et al. Insulin secretory response is
idiopathic skeletal hyperostosis (DISH). comparison of treatment methods and clinical positively associated with the extent of
Osteoarthritis Cartilage 17, 825–828 (2009). outcomes. J. Spinal Disord. Tech. 22, 77–85 ossification of the posterior longitudinal
22. Mader, R. Diffuse idiopathic skeletal (2009). ligament of the spine. J. Bone Joint Surg. 83A,
hyperostosis: a distinct clinical entity. Isr. Med. 41. Westerveld, L. A., van Bemmel, J. C., 1537–1544 (2001).
Assoc. J. 5, 506–508 (2003). Dhert, W. J., Oner, F. C. & Verlaan, J. J. Clinical 60. Kiss, C., Szilagyi, M., Paksy, A. & Poor, G.
23. Fornasier, V. L., Littlejohn, G. O., Urowitz, M. B., outcome after traumatic spinal fractures in Risk factors for diffuse idiopathic skeletal
Keystone, E. C. & Smythe, H. A. Spinal entheseal patients with ankylosing spinal disorders hyperostosis: a case control study.
new bone formation: the early changes of spinal compared with control patients. Spine J. http:// Rheumatology (Oxford) 41, 27–30 (2002).
diffuse idiopathic skeletal hyperostosis. www.doi.org/10.1016/j.spinee.2013.06.038. 61. Sarzi-Puttini, P. & Atzeni, F. New developments in
J. Rheumatol. 10, 934–947 (1983). 42. Littlejohn, J. O., Urowitz, M. B., Smythe, H. A. & our understanding of DISH (diffuse idiopathic
24. Belanger, T. A. & Rowe, D. E. Diffuse idiopathic Keystone, E. C. Radiographic features of the skeletal hyperostosis). Curr. Opin. Rheumatol.
skeletal hyperostosis: musculoskeletal hand in diffuse idiopathic skeletal hyperostosis 16, 287–292 (2004).
manifestations. J. Am. Acad. Orthop. Surg. 9, (DISH). Radiology 140, 623–629 (1981). 62. Miyazawa, N. & Akiyama, I. Diffuse idiopathic
258–267 (2001). 43. Beyeler, C. et al. Diffuse idiopathic skeletal skeletal hyperostosis associated with risk
25. Mader, R. Clinical manifestations of diffuse hyperostosis (DISH) of the shoulder. A cause of factors for stroke. Spine 31, E225–E229
idiopathic skeletal hyperostosis of the cervical shoulder pain? Br. J. Rheumatol. 29, 349–353 (2006).
spine. Semin. Arthritis Rheum. 32, 130–135 (1990). 63. Forestier, J. & Lagier, R. Ankylosing
(2002). 44. Utsinger, P. D., Resnick, D. & Shapiro, R. Diffuse hyperostosis of the spine. Clin. Orthop. 74,
26. Di Girolamo, C. et al. Intervertebral disc lesions skeletal abnormalities in Forestier’s disease. 65–83 (1971).
in diffuse idiopathic skeletal hyperostosis Arch. Intern. Med. 136, 763–768 (1976). 64. Sencan, D., Elden, H., Nacitrahan, V., Sencan, M.
(DISH). Clin. Exp. Rheumatol. 19, 310–312 45. Schlapbach, P. et al. The prevalence of palpable & Kaptanoglu, E. The prevalence of diffuse
(2001). finger joints nodules in diffuse idiopathic idiopathic skeletal hyperostosis in patients with
27. Hutton, C. DISH…. a state not a disease? skeletal hyperostosis (DISH). A controlled study. diabetes mellitus. Rheumatol. Int. 25, 518–521
[editorial]. Br. J. Rheumatol. 28, 277–280 (1989). Br. J. Rheumatol. 31, 531–534 (1992). (2005).
28. Utsinger, P. D. Diffuse idiopathic skeletal 46. Littlejohn, J. O. & Urowitz, M. B. Peripheral 65. Denko, C. W. & Malemud, C. J. Body mass index
hyperostosis. Clin. Rheum. Dis. 11, 325–351 enthesopathy in diffuse idiopathic skeletal and blood glucose: correlations with serum
(1985). hyperostosis (DISH): a radiologic study. insulin, growth hormone, and insulin-like growth
29. Resnick, D. et al. Diffuse idiopathic skeletal J. Rheumatol. 9, 568–572 (1982). factor‑1 levels in patients with diffuse idiopathic
hyperostosis (DISH) [ankylosing hyperostosis of 47. Resnick, D., Shaul, S. R. & Robins, J. M. skeletal hyperostosis (DISH). Rheumatol. Int. 26,
Forestier and Rotes-Querol]. Semin. Arthritis Diffuse idiopathic skeletal hyperostosis (DISH): 292–297 (2006).
Rheum. 7, 153–187 (1978). Forestier’s disease with extraspinal 66. Littlejohn, G. O. & Smythe, H. A. Marked
30. Mata, S. et al. A controlled study of diffuse manifestations. Radiology 115, 513–524 hyperinsulinemia after glucose challenge in
idiopathic skeletal hyperostosis. Clinical (1975). patients with diffuse idiopathic skeletal
features and functional status. Medicine 76, 48. Haller, J. et al. Diffuse idiopathic skeletal hyperostosis. J. Rheumatol. 8, 965–968
104–117 (1997). hyperostosis: diagnostic significance of (1981).
31. Schlapbach, P. et al. Diffuse idiopathic skeletal radiographic abnormalities of the pelvis. 67. Eckertova, M. et al. Impaired insulin secretion
hyperostosis (DISH) of the spine: A cause of Radiology 172, 835–839 (1989). and uptake in patients with diffuse idiopathic
back pain? A controlled study. Br. J. Rheumatol. 49. Shehab, D., Elgazzar, A. H. & Collier, B. D. skeletal hyperostosis. Endocr. Regul. 43,
28, 299–303 (1989). Heterotopic ossification. J. Nucl. Med. 43, 149–155 (2009).
32. Mader, R. et al. Non articular tenderness and 346–353 (2002). 68. Mueller, M. B. et al. Insulin is essential for
functional status in patients with diffuse 50. Gorman, C., Jawad, A. S. M. & Chikanza, I. in vitro chondrogenesis of mesenchymal
idiopathic skeletal hyperostosis. J. Rheumatol. A family with diffuse idiopathic hyperostosis. progenitor cells and influences chondrogenesis
37, 1911–1916 (2010). Ann. Rheum. Dis. 64, 1794–1795 (2005). in a dose-dependent manner. Int. Orthop. 37,
33. Olivieri, I. et al. Diffuse idiopathic skeletal 51. Burges-Armas, J. et al. Ectopic calcification 153–158 (2013).
hyperostosis may give the typical postural among families in the Azores: clinical and 69. Ohlsson, C., Bengtsson, B. A., Isaksson, O. G. P.,
abnormalities of advanced ankylosing spondylitis. radiological manifestations in families with Andereassen, T. T. & Slootweg, M. C. Growth
Rheumatology 46, 1709–1711 (2007). diffuse idiopathic skeletal hyperostosis and hormone and bone. Endocrine Rev. 19, 55–79
34. Baraliakos, X., Listing, J., Buschmann, J., von der chondrocalcinosis. Arthritis Rheum. 54, (1998).
Recke, A. & Braun, J. A comparison of new bone 1340–1349 (2006). 70. Vetter, U. et al. Human fetal and adult
formation in patients with ankylosing spondylitis 52. Kranenburg, H. C. et al. The dog as an animal chondrocytes. Effect of insulinlike growth
and patients with diffuse idiopathic skeletal model for DISH? Eur. Spine J. 19, 1325–1329 factors I and II, insulin, and growth hormone on
hyperostosis. A retrospective cohort study over (2010). clonal growth. J. Clin. Invest. 77, 1903–1908
six years. Arthritis Rheum. 64, 1127–1133 53. Havelka, S. et al. Are DISH and OPLL genetically (1986).
(2012). related? Ann. Rheum. Dis. 60, 902–903 (2001). 71. Denko, C. W., Boja, B. & Moskowitz, R. W. Growth
35. Belanger, T. A. & Rowe, D. E. Diffuse idiopathic 54. Tsukahara, S. et al. COL6A1, the candidate gene factors, insulin-like growth factor‑1 and growth
skeletal hyperostosis: musculoskeletal for ossification of the posterior longitudinal hormone, in synovial fluid and serum of patients
manifestations. J. Am. Acad. Orthop. Surg. 9, ligament, is associated with diffuse idiopathic with rheumatic disorders. Osteoarthritis Cartilage
258–267 (2001). skeletal hyperostosis in Japanese. Spine 30, 4, 245–249 (1996).
36. Laroche, M. et al. Lumbar and cervical stenosis. 2321–2324 (2005). 72. Denko, C. W., Boja, B. & Malemud, C. J. Intra-
Frequency of the association, role of the 55. Shingyouchi, O., Nagahama, A. & Niida, M. erythrocyte deposition of growth hormone in
ankylosing hyperostosis. Clin. Rheumatol. 11, Ligamentous ossification of the cervical spine in rheumatic diseases. Rheumatol. Int. 23, 11–14
533–535 (1992). the late middle-aged Japanese men. Its relation (2003).
37. Liu, P. et al. Spinal trauma in mainland China to body mass index and glucose metabolism. 73. el Miedany, Y. M., Wassif, G. & el Baddini, M.
from 2001 to 2007: An epidemiological study Spine 21, 2474–2478 (1996). Diffuse idiopathic skeletal hyperostosis (DISH):
based on a nationwide database. Spine (Phila Pa 56. Littlejohn, G. O. Insulin and new bone formation is it of vascular etiology? Clin. Exp. Rheumatol.
1976) 37, 1310–1315 (2012). in diffuse idiopathic skeletal hyperostosis. Clin. 18, 193–200 (2000).
38. Caron, T. et al. Spine fractures in patients with Rheumatol. 4, 294–300 (1985). 74. Nesher, G. & Zuckner, J. Rheumatologic
ankylosing spinal disorders. Spine (Phila Pa 57. Denko, C. W., Boja, B. & Moskowitz, R. W. complications of vitamin A and retinoids. Semin.
1976) 35, E458–E464 (2010). Growth promoting peptides in osteoarthritis Arthritis Rheum. 24, 291–296 (1995).
39. Westerveld, L. A., Verlaan, J. J. & Oner, F. C. and diffuse idiopathic skeletal hyperostosis 75. Abiteboul, M., Arlet J., Sarrabay, M. A.,
Spinal fractures in patients with ankylosing —insulin, insulin-like growth factor‑I, growth Mazières, B. & Thouvenot, J. P. Etude du
spinal disorders: A systematic review of the hormone. J. Rheumatol. 21, 1725–1730 metabolisme de la vitamine A au cours de la
literature on treatment, neurological status and (1994). maladie hyperostosique de Forestier et Rote’s-
complications. Eur. Spine J. 18, 145–156 58. Vezyroglou, G., Mitropoulos, A., Kyriazis, N. & Querol. Rev. Rhum. Ed. Fr. 53, 143–145
(2009). Antoniadis, C. A metabolic syndrome in diffuse (1986).

NATURE REVIEWS | RHEUMATOLOGY ADVANCE ONLINE PUBLICATION  |  9

© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS

76. Ling, T. C., Parkin, G., Islam, J., Seukeran, D. C. & synthesis of bone morphogenetic proteins of skeletal hypertrophy and degenerative disk
Cunliffe, W. J. What is the cumulative effect of spinal ligament cells derived from patients with disease. J. Chiropr. Med. 11, 293–299 (2012).
long-term, low dose isotretinoin on the ossification of the posterior longitudinal 100. El Garf, A. & Khater, R. Diffuse idiopathic skeletal
development of DISH? Br. J. Dermatol. 144, ligaments. Bone 33, 475–484 (2003). hyperostosis (DISH): a clinicopathological study
630–632 (2001). 88. Ohishi, H. et al. Role of prostaglandin I2 in the of the disease pattern in Middle Eastern
77. Aeberli, D., Schett, G., Eser, P., Seitz, M. & gene expression induced by mechanical stress populations. J. Rheumatol. 11, 804–807 (1984).
Villiger, P. M. Serum Dkk‑1 levels of DISH in spinal ligament cells derived from patients 101. Hochberg, M. C. et al. American College of
patients are not different from healthy controls. with ossification of the posterior longitudinal Rheumatology recommendations for the use
Joint Bone Spine 78, 422–423 (2011). ligament. J. Pharmacol. Exp. Ther. 305, 818–824 of nonpharmacologic and pharmacologic
78. Daoussis, D. & Andonopoulos, A. P. The emerging (2003). therapies in osteoarthritis of the hand, hip,
role of Dickkopf‑1 in bone biology: is it the main 89. Iwasawa, T. et al. Pathophysiological role of and knee. Arthritis Care Res. 64, 465–474
switch controlling bone and joint remodeling? endothelin in ectopic ossification of human (2012).
Semin. Arthritis Rheum. 41, 170–177 (2011). spinal ligaments induced by mechanical stress. 102. Roth, S. H. & Shainhouse, J. Z. Efficacy and
79. Senolt, L. et al. Low circulating Dickkopf‑1 and its Calcif. Tissue Int. 79, 422–430 (2006). safety of a topical diclofenac solution (pennsaid)
link with severity of spinal involvement in diffuse 90. Kasperk, C. H. et al. Endothelin‑1 is a potent in the treatment of primary osteoarthritis of the
idiopathic skeletal hyperostosis. Ann. Rheum. regulator of human bone cell metabolism. Calcif. knee: a randomized, double-blind, vehicle-
Dis. 71, 71–74 (2012). Tissue Int. 60, 368–374 (1997). controlled clinical trial. Arch. Intern. Med. 164,
80. Mader, R. & Verlaan, J. J. Bone: Exploring factors 91. Carile, L., Verdone, F., Aiello, A. & Buongusto, G. 2017–2023 (2004).
responsible for bone formation in DISH. Nat. Diffuse idiopathic skeletal hyperostosis and 103. Lithell, H. O. L. Effect of antihypertensive drugs
Rev. Rheumatol. 8, 10–12 (2011). situs viscerum inversus. J. Rheumatol. 16, on insulin, glucose, and lipid metabolism.
81. Kosaka, T., Imakiire, A., Mizuno, F. & 1120–1122 (1989). Diabetes Care 14, 203–209 (1991).
Yamamoto, K. Activation of nuclear factor κB at 92. Smythe, H. A. The mechanical pathogenesis of 104. Carlson, M. L., Archibald, D. J., Graner, D. E. &
the onset of ossification of the spinal ligaments. generalized osteoarthritis. J. Rheumatol. Kasperbauer, J. L. Surgical management of
J. Orthop. Sci. 5, 572–578 (2000). 10 (Suppl. 9), 11–12 (1983). dysphagia and airway obstruction in patients
82. Inaba, T. et al. Enhanced expression of platelet- 93. Arlet, J. & Mazieres, B. La maladie with prominent ventral cervical osteophytes.
derived growth factor-β receptor by high glucose. hyperostosique. Rev. Mdd. Interne. 6, 553–564 Dysphagia 26, 34–40 (2011).
Involvement of platelet-derived growth factor in (1985). 105. Urrutia, J. & Bono, C. M. Long-term results of
diabetic angiopathy. Diabetes 45, 507–512 94. Mader, R. et al. Developing new classification surgical treatment of dysphagia secondary to
(1996). criteria for diffuse idiopathic skeletal cervical diffuse idiopathic skeletal hyperostosis.
83. Pfeiffer, A., Middelberg-Bisping, K., Drewes, C. hyperostosis: back to square one. Rheumatology Spine J. 9, e13–e17 (2009).
& Schatz, H. Elevated plasma levels of (Oxford) 52, 326–330 (2013). 106. Guillemin, F., Mainard, D., Rolland, H. &
transforming growth factor-β1 in NIDDM. 95. Olivieri, I. et al. Diffuse idiopathic skeletal Delagoutte, J. P. Antivitamin K prevents
Diabetes Care 19, 1113–1117 (1996). hyperostosis: differentiation from ankylosing heterotopic ossification after hip arthroplasty in
84. Kon, T. et al. Bone morphogenetic protein‑2 spondylitis. Curr. Rheumatol. Rep. 11, 321–328 diffuse idiopathic skeletal hyperostosis: a
stimulates differentiation of cultured spinal (2009). retrospective study in 67 patients. Acta Orthop.
ligament cells from patients with ossification of 96. Mader, R. Diffuse idiopathic skeletal hyperostosis: Scand. 66, 123–126 (1995).
the posterior longitudinal ligament. Calcif. Tissue isolated involvement of cervical spine in a young 107. Knelles, D. et al. Prevention of heterotopic
Int. 60, 291–296 (1997). patient. J. Rheumatol. 31, 620–621 (2004). ossification after total hip replacement: a
85. Tanaka, H. et al. Involvement of bone 97. Al-Herz, A., Snip, J. P., Clark, B. & Esdaile, J. M. prospective, randomized study using
morphogenic protein‑2 (BMP‑2) in the Exercise therapy for patients with diffuse acetylsalicylic acid, indomethacin and fractional
pathological ossification process of the spinal idiopathic skeletal hyperostosis. Clin. or single-dose irradiation. J. Bone Joint Surg. Br.
ligament. Rheumatology 40, 1163–1168 (2001). Rheumatol. 27, 207–210 (2008). 79, 596–602 (1997).
86. Zebboudj, A. F., Imura, M. & Bostrom, K. Matrix 98. Troyanovich, S. J. & Buettner, M. A structural
GLA protein, a regulatory protein for bone chiropractic approach to the management of Author contributions
morphogenetic protein‑2. J. Biol. Chem. 8, diffuse idiopathic skeletal hyperostosis. All authors made substantial contributions to
4388–4394 (2002). J. Manipulative Physiol. Ther. 26, 202–206 (2003). discussions of content, writing, and reviewing/
87. Tanno, M., Furukawa, K. I., Ueyama, K., 99. Roberts, J. A., Tristy, M. & Wolfe, M. A. editing the manuscript before submission. In
Harata, S. & Motomura, S. Uniaxial cyclic Chiropractic management of a veteran with lower addition, R. Mader and J.‑J. Verlaan researched data
stretch induces osteogenic differentiation and back pain associated with diffuse idiopathic for the article.

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